Although it is well-documented that animals with high plasma levels of lipoproteins containing apo-B develop premature atherosclerosis, the exact mechanism is still unknown. The response-to-retention hypothesis holds that low density lipoproteins (LDL) and other atherogenic apo-B containing lipoproteins are retained or trapped in the subendothelium by interacting with intimal proteoglycans initiating early atherosclerosis. Our preliminary evidence shows that we can design and genetically alter atherogenic lipoproteins in such a way that they will not bind to artery wall proteoglycans. If the interaction with proteoglycans is a significant component in the subendothelial retention of lipoproteins, these altered lipoproteins therefore should not be retained in the subendothelium. Further, if binding to proteoglycans is the initial or a significant step in atherogenesis, then high levels of genetically altered of genetically altered defective-proteoglycan-binding LDL will be much less atherogenic than equivalent levels of normal LDL. Using transgenic mouse models we will first determine if proteoglycan-defective-binding LDL causes less atherosclerosis than normal LDL animals fed a high cholesterol diet. If mouse atherosclerosis studies indicate defective-proteoglycan-binding LDL are less atherogenic, we will investigate the mechanism with presumption that proteoglycan-binding LDL are less atherogenic, we will investigate the mechanism with the presumption that proteoglycan-defective-binding LDL are poorly retained in the subendothelium. Using gene-targeted technology, we will generate proteoglycan-defective-binding apo-B48 to determine if the atherogenesis causes by B48-containing lipoproteins is due to their binding to proteoglycans. Finally, we will determine if lipoprotein lipase contributes to atherosclerosis in a direct bridging role by enhancing the binding of LDL with proteoglycans. These studies should help clarify how LDL and other apo-B-containing lipoproteins cause atherosclerosis. Moreover, if the inhibition of LDL binding to proteoglycans is anti- atherogenic, then the use of small molecules to inhibit LDL binding to proteoglycans may have therapeutic potential to reduce or prevent atherosclerosis.